High-risk human papillomaviruses (HPVs), including HPV16, are present in nearly all cervical carcinomas. HPV-induced carcinogenesis is a result of the dysregulated expression of HPV E6 and E7. Because HPV genome replication and virion production occur in the most differentiated layers of the epithelium, E6 and E7 subvert pathways that signal growth arrest during differentiation; for instance, high-risk HPV E6 and E7 compromise the p53 and pRB tumor suppressors, respectively. Preliminary evidence shows that the HPV16 E7 oncoprotein can interact with E2F6, a specific repressor of transcription of cell cycle regulated genes. This proposal aims to characterize the interaction by co-immunoprecipitations, mutant mapping, and reporter assays. Changes in E2F6-mediated repression by E7 will be determined using Northern and ChIP analyses. The central hypothesis of this proposal is that E7 relieves E2F6-mediated transcriptional repression, thus providing yet another layer of control by which HPV ensures that the infected host cell remains S-phase competent, which is vital for viral genome replication and likely contributes to cellular transformation. These studies will further the understanding of how viral proteins interact with cellular factors to induce cancer. [unreadable] [unreadable] [unreadable] [unreadable]